West China School of Public Health and West China Fourth Hospital, Sichuan University, 17#, Section 3, Renmin Nan Road, Chengdu, 610041, Sichuan, People's Republic of China.
Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, West China School of Public Health, Sichuan University, Chengdu, People's Republic of China.
Sci Rep. 2021 Jun 28;11(1):13404. doi: 10.1038/s41598-021-92875-9.
Cervical cancer continues to impose a heavy burden worldwide, and human papilloma virus (HPV) infection, especially persistent infection with type 16 (HPV-16), is known to be the primary etiological factor. Therapeutic vaccines are urgently needed because prophylactic vaccines are ineffective at clearing pre-existing HPV infection. Here, two recombinant Listeria strains (LMΔ-E6E7 & LIΔ-E6E7) with deletions of the actA and plcB genes, expressing the shuffled HPV-16 E6E7 protein were constructed. The strains were delivered into the spleen and liver by intravenous inoculation, induced antigen-specific cellular immunity and were eliminated completely from the internal organs several days later. Intravenously treating with single strain for three times, or with both strains alternately for three times significantly reduced the tumor size and prolonged the survival time of model mice. Combination immunotherapy with two strains seemed more effective than immunotherapy with single strain in that it enhanced the survival of the mice, and the LMΔ-E6E7-prime-LIΔ-E6E7-boost strategy showed significant stronger efficacy than single treatment with the LIΔ-E6E7 strain. The antitumor effect of this treatment might due to its ability to increase the proportion of CD8 T cells and reduce the proportion of T regulatory cells (Tregs) in the intratumoral milieu. This is the first report regarding Listeria ivanovii-based therapeutic vaccine candidate against cervical cancer. Most importantly we are the first to confirm that combination therapy with two different recombinant Listeria strains has a more satisfactory antitumor effect than administration of a single strain. Thus, we propose a novel prime-boost treatment strategy.
宫颈癌在全球范围内仍造成沉重负担，人乳头瘤病毒（HPV）感染，尤其是 16 型（HPV-16）持续性感染，被认为是主要的病因学因素。由于预防性疫苗不能清除已有的 HPV 感染，因此迫切需要治疗性疫苗。在这里，构建了两种缺失 actA 和 plcB 基因、表达 HPV-16 E6E7 蛋白的重组李斯特菌（LMΔ-E6E7 和 LIΔ-E6E7）菌株。通过静脉接种将这些菌株递送到脾脏和肝脏，诱导抗原特异性细胞免疫，并在几天后从内脏器官中完全清除。三次静脉内给予单种菌株或两种菌株交替给予三次，可显著减小肿瘤大小并延长模型小鼠的存活时间。两种菌株联合免疫治疗似乎比单一菌株免疫治疗更有效，因为它提高了小鼠的存活率，并且 LMΔ-E6E7-prime-LIΔ-E6E7-boost 策略比单独使用 LIΔ-E6E7 菌株治疗显示出更强的疗效。这种治疗的抗肿瘤作用可能与其增加肿瘤内 CD8 T 细胞比例和降低调节性 T 细胞（Tregs）比例的能力有关。这是首次报道基于李斯特菌伊万诺夫斯基的治疗性宫颈癌疫苗候选物。最重要的是，我们首次证实，与单一菌株给药相比，两种不同重组李斯特菌菌株联合治疗具有更满意的抗肿瘤效果。因此，我们提出了一种新的免疫原性增强治疗策略。
